Incidence of Dementia in Relation to Stroke and the Apolipoprotein E ε4 Allele in the Very Old

Abstract

Background and Purpose-Both stroke and the apolipoprotein E (APOE) ⑀4 allele increase the risk of dementia. However, the interaction between stroke and APOE on dementia is still unclear. We addressed this topic by using a longitudinal design. Methods-We followed up a community cohort of 1301 subjects aged Ն75 years, who did not have dementia at baseline.Among them, 92 subjects had a history of stroke (from 3 months to 16 years before baseline interview). After the 3-year follow-up, 224 dementia cases had been diagnosed. During the period of follow-up, 91 subjects had a first occurrence of stroke (incident stroke). The APOE genotype was known for 985 subjects. Cox proportional hazards regression models were constructed to estimate the risk for dementia in terms of relative risks (RRs) for stroke and the APOE ⑀4 allele, with adjustment for age, sex, education, systolic blood pressure, antihypertensive medication use, and heart disease. Results-In the entire study population, RRs for dementia related to history of stroke and incident stroke were 1.7 (95% CI, 1.1 to 2.6) and 2.4 (95% CI, 1.6 to 3.5), respectively, after adjustment for all potential confounders. Subjects with stroke that occurred within 3 years before baseline had RR of 2.4 (95% CI, 1.4 to 4.2), whereas those with stroke occurring Ͼ3 years before baseline had RR of dementia of 1.1 (95% CI, 0.6 to 2.3). Among those with APOE information, individuals with only history of stroke (that occurred within 3 years before baseline) had RR of 3.1 (95% CI, 1.4 to 6.6), individuals with only the APOE ⑀4 allele had RR of 1.7 (95% CI, 1.1 to 2.5), and individuals with both factors had RR of 5.3 (95% CI, 2.1 to 13.4). The corresponding figures when incident stroke was examined instead of history of stroke were 2.3 (95% CI, 1.3 to 4.1), 1.7 (95% CI, 1.1 to 2.4), and 4.6 (95% CI, 2.0 to 10.6), respectively. The RR of interaction term for history of stroke and APOE ⑀4 was 1.1 (95% CI, 0.3 to 3.8; Pϭ0.8). The corresponding figure was 1.2 (95% CI, 0.4 to 4.4; Pϭ0.7) for incident stroke and APOE ⑀4. Furthermore, the RRs of dementia without any stroke and dementia with stroke in relation to APOE ⑀4 were 1.6 (95% CI, 1.1 to 2.3) and 1.2 (95% CI, 0.6 to 2.4), respectively. In addition, the APOE ⑀4 allele was not significantly related to the occurrence of stroke (RRϭ0.8; 95% CI, 0.5 to 1.5). Conclusions-A relatively fresh stroke is a risk factor for dementia. APOE ⑀4 increases the risk of dementia without stroke but not dementia with stroke. Our data do not support a multiplicative effect of stroke and the APOE ⑀4 allele on the risk of dementia. However, both factors seem to have an additive effect on the risk of dementia. The APOE ⑀4 allele does not increase the risk of stroke in this Swedish elderly population. (Stroke. 2000;31:53-60.)

Epidemiological Studies of the Effect of Stroke on Incident Dementia

“…Nine studies reported an estimate of the effect of a history of stroke on the risk of dementia. [13][14][15][16][17][18][19][20][21] Seven studies reported the effect of incident stroke on dementia risk in cohorts that were initially both stroke-and dementia-free. 13,15,16,[22][23][24][25] Rochester study investigators 26 estimated standardized morbidity ratios for dementia by comparing dementia incidence rates in a population with incident stroke with those found in the general Rochester population and so this study is included despite no direct control comparison.…”

“…Zhu et al 15 report no excess risk of dementia incidence in participants whose stroke occurred Ͼ3 years before baseline, although this analysis was restricted to those without recurrent stroke in the follow-up period. Those with stroke within 3 years of baseline but no recurrent stroke had twice the risk of dementia.…”

“…The delay between stroke and baseline assessment was found by both studies in which it was directly examined 15,26 to affect the risk of dementia incidence with more recent strokes having a greater effect. Zhu et al 15 report no excess risk of dementia incidence in participants whose stroke occurred Ͼ3 years before baseline, although this analysis was restricted to those without recurrent stroke in the follow-up period.…”

“…Estimates of the effect of incident stroke were also variable, 13,15,16,[22][23][24][25] but the effect of an incident stroke on incident dementia is higher than the effect of a history of stroke, suggesting that the excess risk of stroke is greatest close to stroke occurrence.…”

Modulation of Astrocytic Activation by Arundic Acid (ONO-2506) Mitigates Detrimental Effects of the Apolipoprotein E4 Isoform after Permanent Focal Ischemia in Apolipoprotein E Knock-in Mice

“…Apolipoprotein E is mainly produced by astrocytes in the CNS (Fujita et al, 1999), and it has been shown to modulate the endogenous CNS inflammatory response in an isoform-specific manner (Barger and Harmon, 1997;Laskowitz et al, 2001;Lynch et al, 2001Lynch et al, , 2003. While an association between the APOE e4 allele and exacerbation of cerebral infarction has been supported by some clinical studies (Kim et al, 2003;Margaglione et al, 1998;McCarron et al, 1999), contradictory results have also been reported (Basun et al, 1996;Frikke-Schmidt et al, 2001;Zhu et al, 2000). Based on a reduced frequency of the APOE e4 allele in patients who had survived a previous stroke (Basun et al, 1996), Laskowitz et al (1998) surmised that APOE genotype may not alter risk for stroke, but it may alter recovery once it occurs.…”